Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology

383 Pages·2020·27.26 MB·English

by  Hilmar Weinmann, Craig Crews

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Drug Discovery
Protein Degradation with
New Chemical Modalities
Successful Strategies in Drug Discovery
and Chemical Biology
Edited by Hilmar Weinmann and Craig M. Crews

i
Protein Degradation with New Chemical Modalities

Successful Strategies in Drug Discovery and Chemical Biology
ii
Drug Discovery Series

Editor- in- chief
David Thurston, King’s College London, UK
Series editors:
David Fox, Vulpine Science and Learning, UK
Ana Martinez, Centro de Investigaciones Biologicas-C SIC, Spain
David Rotella, Montclair State University, USA
Hong Shen, Roche Innovation Center Shanghai, China
Editorial advisor:
Ian Storer, AstraZeneca, UK
Titles in the Series:
1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
4: Accounts in Drug Discovery
5: New Frontiers in Chemical Biology
6: Animal Models for Neurodegenerative Disease
7: Neurodegeneration
8: G Protein- Coupled Receptors
9: Pharmaceutical Process Development
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies in Medicinal Chemistry
12: New Horizons in Predictive Toxicology
13: Drug Design Strategies: Quantitative Approaches
14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi- Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico- Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti- Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
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30: Computational Approaches to Nuclear Receptors
31: Traditional Chinese Medicine
32: Successful Strategies for the Discovery of Antiviral Drugs
33: Comprehensive Biomarker Discovery and Validation for Clinical Application
34: Emerging Drugs and Targets for Parkinson’s Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms
36: Biotherapeutics: Recent Developments using Chemical and Molecular
Biology
37: Inhibitors of Molecular Chaperones as Therapeutic Agents
38: Orphan Drugs and Rare Diseases
39: Ion Channel Drug Discovery
40: Macrocycles in Drug Discovery
41: Human- based Systems for Translational Research
42: Venoms to Drugs: Venom as a Source for the Development of Human
Therapeutics
43: Carbohydrates in Drug Design and Discovery
44: Drug Discovery for Schizophrenia
45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New
Therapies
46: Green Chemistry Strategies for Drug Discovery
47: Fragment- Based Drug Discovery
48: Epigenetics for Drug Discovery
49: New Horizons in Predictive Drug Metabolism and Pharmacokinetics
50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation
51: Nanomedicines: Design, Delivery and Detection
52: Synthetic Methods in Drug Discovery: Volume 1
53: Synthetic Methods in Drug Discovery: Volume 2
54: Drug Transporters: Role and Importance in ADME and Drug Development
55: Drug Transporters: Recent Advances and Emerging Technologies
56: Allosterism in Drug Discovery
57: Anti- aging Drugs: From Basic Research to Clinical Practice
58: Antibiotic Drug Discovery: New Targets and Molecular Entities
59: Peptide-b ased Drug Discovery: Challenges and New Therapeutics
60: Drug Discovery for Leishmaniasis
61: Biophysical Techniques in Drug Discovery
62: Acute Brain Impairment Through Stroke: Drug Discovery and Translational
Research
63: Theranostics and Image Guided Drug Delivery
64: Pharmaceutical Formulation: The Science and Technology of Dosage Forms
65: Small-m olecule Transcription Factor Inhibitors in Oncology
66: Therapies for Retinal Degeneration: Targeting Common Processes
67: Kinase Drug Discovery: Modern Approaches
68: Advances in Nucleic Acid Therapeutics
69: MicroRNAs in Diseases and Disorders: Emerging Therapeutic Targets
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70: Emerging Drugs and Targets for Multiple Sclerosis
71: Cytotoxic Payloads for Antibody– Drug Conjugates
72: Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing,
and Controls
73: Anti- fibrotic Drug Discovery
74: Protein Degradation with New Chemical Modalities: Successful Strategies
in Drug Discovery and Chemical Biology
How to obtain future titles on publication:
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For further information please contact:
Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: [phone], Fax: [phone],
Email: [email protected]
Visit our website at www.rsc.org/ books
v
Protein Degradation with New

Chemical Modalities
Successful Strategies in Drug Discovery
and Chemical Biology
Edited by
Hilmar Weinmann
Janssen Pharmaceutica N.V., Belgium
Email: [email protected]
and
Craig Crews
Yale University, USA
Email: [email protected]
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Drug Discovery Series No. 74
Print ISBN: 978- 1- 78801- 686- 5
PDF ISBN: 978- 1- 83916- 069- 1
EPUB ISBN: 978- 1- 83916- 077- 6
Print ISSN: 2041– 3203
Electronic ISSN: 2041– 3211
A catalogue record for this book is available from the British Library
© The Royal Society of Chemistry 2021
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Preface

The modulation of proteins within living cells plays a major role in the treat-
ment of a multitude of severe diseases. Small- molecule drugs can be used as
the standard approach in many cases. Nevertheless, there are still some limi-
tations related to small- molecule inhibitors which restrict their utility in cer-
tain protein classes. Many of these compounds act through occupying active
sites. However, many proteins, such as scaffolding proteins or transcription
factors, lack such active sites and therefore are often considered to possess
poor druggability. Other limitations of current small- molecule drugs are
induced target protein mutations resulting in drug resistance or compensa-
tory feedback activation of downstream signaling while inhibiting one spe-
cific target. Long-t erm target protein inhibition may lead to compensatory
protein overexpression and protein accumulation which may lead to incom-
plete inhibition. Therefore, the search for innovative treatment methods and
new modalities for intracellular modulation of proteins is a highly active field
of current research. The aim of this book is to give an overview on promising
recent approaches to overcome the limitations of classical small molecules
with novel modalities for protein degradation and their applications in chem-
ical biology and drug discovery.
Proteolysis- targeting chimeras (PROTACs) are an area of induced protein
degradation, which makes use of hetero-b ifunctional molecules that induce
a ligand to bind with the target protein, another ligand to recruit an E3 ubiq-
uitin ligase, and a linker in between the two ligands. Once the ternary com-
plex consisting of the target protein, the PROTAC and the E3 ligase is formed,
the recruited E3 ligase will employ an E2 ubiquitin- conjugating enzyme to
transfer ubiquitin to the surface of the targeted protein. A polyubiquitination
signal will be recognized by the proteasome to initiate the degradation of the
Protein Degradation with New Chemical Modalities: Successful Strategies in
Drug Discovery and Chemical Biology
Drug Discovery Series No. 74
Edited by Hilmar Weinmann and Craig Crews
© The Royal Society of Chemistry 2021
Published by the Royal Society of Chemistry, www.rsc.org
vii
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viii Preface
targeted protein. PROTACs have been employed to induce the degradation of
a variety of proteins, including kinases, nuclear receptors and transcriptional
factors, as well as regulatory proteins.
In the first chapter, Philipp M. Cromm, Craig M. Crews and Hilmar
Weinmann describe the basic principles and summarize the historic devel-
opment of PROTAC-m ediated target degradation as a potential paradigm
changer in drug discovery.
David Zollman and Alessio Ciulli describe the structural and biophysical
principles of degrader ternary complexes. Degraders predominantly recruit
a target protein to an E3 ubiquitin ligase and form with them a ternary com-
plex, which triggers target ubiquitination and subsequent proteasomal deg-
radation. The structural, thermodynamic and kinetic features of the ternary
complexes determine the speed, potency, selectivity and durability of their
cellular degradation activity. The authors illustrate how structural biology and
biophysics are rapidly impacting the field and describe the main assays that
are being developed and used to study PROTAC ternary complexes.
In Chapter 3, Behnam Nabet and Nathanael S. Gray report on the immedi-
ate and selective control of protein abundance using the dTAG system. The
dTAG technology platform uses hetero-b ifunctional small- molecule degrad-
ers to co- opt the endogenous cellular degradation machinery to rapidly and
reversibly deplete FKBP12F36V- tagged target proteins. The dTAG system and
related tag- based degradation strategies have the potential to become essen-
tial tools for pre- clinical target validation and mechanistic biological investi-
gation in cellular and mouse models of development and disease.
Several examples of PROTACs with in vivo efficacy in pre- clinical studies
have been disclosed recently. While building pharmacokinetic (PK)/p harma-
codynamic (PD) relationships is recognized as a key activity in small-m olecule
drug discovery to support translation from the research to clinical phases,
there has been a lack of reports describing this for PROTACs despite their
huge potential as therapeutics. John D. Harling, Paul Scott-S tevens and Lu
Gaohua discuss the unique mechanism of action of PROTACs and how this
introduces additional factors which may need to be considered in the devel-
opment of the PK/P D relationship, including how PBPK/P D modeling can be
used to deliver human dose predictions with PROTACs.
In the last few years interest in the potential of small-m olecule therapeu-
tics capable of redirecting the cellular ubiquitin– proteasome machinery to
destroy specific proteins has increased drastically. While one approach uti-
lizes hetero- bifunctional ligands capable of simultaneously binding both
an E3 ubiquitin ligase and the target protein, another class of molecules,
termed CELMoDs (cereblon E3 ligase modulating drugs), are low molecular
weight small molecules that induce the degradation of specific protein tar-
gets by binding to the cereblon-C RL4 E3 ubiquitin ligase and scaffolding
direct protein– protein interactions to the target protein. These molecules are
capable of recruiting undruggable and even unligandable targets through a
so- called “molecular glue” mechanism. Mary E. Matyskiela, Thomas Clayton,
Joel W. Thompson, Christopher Carroll, Leslie Bateman, Laurie LeBrun and